Total synthesis of (+)-trans- dihydronarciclasine from (+)-7-azabicyclo[2.2.1]heptanone

Article abstract of DOI:10.1016/j.tet.2018.08.016

A concise asymmetric total synthesis of Amaryllidaceae alkaloid (+)-trans-dihydronarciclasine is accomplished starting from optically pure 7-azabicyclo[2.2.1]heptanone scaffold in 13 linear steps. Key features of the strategy include substrate-directed st

Full text of DOI:10.1016/j.tet.2018.08.016

Accepted Manuscript
Total synthesis of (+)-trans- dihydronarciclasine from (+)-7-
azabicyclo[2.2.1]heptanone
Ganesh Pandey, Rushil Fernandes, Debasis Dey, Binoy Majumder
PII:
S0040-4020(18)30967-0
10.1016/j.tet.2018.08.016
TET 29736
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 June 2018
Revised Date: 3 August 2018
Accepted Date: 13 August 2018
Please cite this article as: Pandey G, Fernandes R, Dey D, Majumder B, Total synthesis of (+)-trans-
dihydronarciclasine from (+)-7-azabicyclo[2.2.1]heptanone, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.08.016.
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Total Synthesis of (+)-trans- Dihydronarciclasine from (+)-7-
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Azabicyclo[2.2.1]heptanone
Ganesh Pandey,*a Rushil Fernandes,a Debasis Dey,a and Binoy Majumderb
a Molecular Synthesis laboratory, Center of Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences
Campus, Raebareli Road, Lucknow- 226014(U. P.), India.
b
Division of Organic Chemistry, National Chemical Laboratory, Pune-411008.

1
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Tetrahedron
journal homepage: www.elsevier.com
Total synthesis of (+)-trans-Dihydronarciclasine from (+)-7-Azabicyclo[2.2.1]hep
tanone
Ganesh Pandey,*a Rushil Fernandes, a Debasis Dey, a and Binoy Majumder b
a Molecular Synthesis laboratory, Center of Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Raebareli Road,
Lucknow- 226014(U. P.), India.
bDivision of Organic Chemistry, National Chemical Laboratory, Pune-411008.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise asymmetric total synthesis of Amaryllidaceae alkaloid (+)-trans-dihydronarciclasine
is accomplished starting from optically pure 7-azabicyclo[2.2.1]heptanone scaffold in 13 linear
steps. Key features of the strategy include substrate-directed stereoselective installation of the
trans B-C ring junction and regioselective Wacker-type internal olefin oxidation to provide a
rapid access to all hydroxyl functionalities over the key cyclohexane ring in a stereocontrolled
manner.
Available online
Keywords:
Amaryllidaceae alkaloids
(+)-trans-dihydronarciclasine
7-deoxy-pancrastatin
2009 Elsevier Ltd. All rights reserved
.
trans-B-C ring junction stereochemistry
Wacker-type internal olefin oxidation
1. Introduction
In continuation with our synthetic programme, concerning
with the synthesis of Amaryllidaceae class of alkaloids, herein
we report an account of the total synthesis of (+)-trans-
dihydronarciclasine (1) which belongs to the family of natural
phenanthridone alkaloids, a subclass of the Amaryllidaceae
alkaloids. Alkaloids derived from the plants of the
Amaryllidaceae family, have long been known as a source of the
pharmacologically potent molecules.1 The syntheses of
isocarbostyril alkaloids (+)-trans-dihydronarciclasine (1) and its
congeners 7-deoxy-trans-dihydro narciclasine (2), narciclasine
(3), lycoricidine (4), pancratistatin (5) and 7-deoxy-pancrastatin
(6) have attracted intense research interest due to their potent
Figure 1. (+)-trans-Dihydronarciclasine (1) and related natural
phenanthridone alkaloids, a subclass of Amaryllidaceae family.
This profound bioactivity profile along with the challenging
structural features, which involves
a highly oxygenated
phenanthridone core with five contiguous stereocentres, is
adduced to persuade in developing the synthesis of this potential
anti-cancer drug, which is structurally related to natural
phenanthridone alkaloids. Though (+)-trans-dihydronarciclasine
has been the focus of a number of racemic,7 chiral8 and
semisynthetic9 syntheses, as of other Amaryllidaceae
isocarbostyril alkaloids,1d,10 but a scalable synthetic route
providing alkaloids in gram quantities and a general approach
towards the entire series of these isocarbostyril alkaloids remain
elusive.
2
antineoplastic and highly significant antiviral activity. (+)-
trans-Dihydronarciclasine (1) was first discovered in 1975 as a
minor products of hydrogenation of naturally-occurring
narciclasine (3),3 however, it was later isolated by Pettit et al. in
1990 from Zephyranthes candida.4 A very recent report
published by National Cancer Institute (NCI,USA) mentions that
(+)-trans-dihydronarciclasine has highest
potency against
selected cancer cell lines among all these phenanthridone family.5
Recent studies have also revealed its remarkable antiviral activity
against the flaviviruses and a remarkable anti-Zika virus
acitivity,6 further emphasizing its tremendous pharmacological
potential.
We recently executed
a scalable synthesis of (+)-7-
deoxypancratistatin (6),11 that could shepherd to develop an
efficient synthetic route towards the total synthesis of
Amaryllidaceae
alkaloids
from
a
common
7-

2
Tetrahedron
ACCEPTED MANUSCRIPT
azabicyclo[2.2.1]heptanone scaffold.11 In this note, we have
consequence, anionic rearrangement of 11 using MeMgBr as a
sought to extend our strategy for the synthesis of 1 from 9 in a
concise synthetic sequence.
base opened the ring furnishing 12. It provided the required
amino and aryl functionality in stereocontrolled manner to obtain
the lactam moiety present in the B ring and an embedded olefin
for further functionalization. Desulfonylation of 12 with sodium
naphthalenide (Na-Nap) produced 8 in 93% yield.
On searching the biological profile of Amaryllidaceae
alkaloids, we recognized that the specific biological activities of
this class of alkaloids are related to their specific stereochemical
arrangements of the contiguous hydroxyl groups over the
periphery of densely functionalized cyclohexane ring and also the
trans-B-C ring junction stereochemistry of the associated
ring.2l,6b,9a,12 The trans B-C ring junction stereochemistry also
entails the high biological activity of these types of alkaloids
which offers a valuable synthetic challenge that has captivated
the attention to synthetic organic chemist towards these alluring
synthetic target.
MgBr
MeO
O
Boc
N
O
H
H
10
Boc
N
(i) NaH, Ts2O, THF, 0 °C, 30 min
(ii) 10, CuI (5 mol%), THF, rt
SO2Ph
SO2Ph
(iii) H2, Pd-C, MeOH, rapid stirring, rt
O
OMe
O
9
O
11
From the perspective of retrosynthetic analysis of 1, as
outlined in the Scheme 1, the prime task is setting up the key
cyclohexane ring C containing five contiguous stereocenters with
proper stereochemical arrangement and associated trans B-C ring
junction stereochemistry. After systematic installation of all the
hydroxyl functionality along with the required aryl and amino
groups, the intermediate A would be ready for the cyclisation to
construct B ring through modified Bischler-Napieralsky reaction.
The cis-geometry of C3 and C4 hydroxy groups provoked us to
employ stereospecific dihydroxylation of an olefinic double bond
in B which would be amenable by other functionalities installed
at the outset of our synthetic programme. The synthesis of the
desired advanced intermediate B was visualized by relocating the
olefin present in the cyclohexane ring of 8 through a sequential
double oxidation followed by reduction protocol. The synthesis
of the intermediate 8 would be the consequence of our ongoing
PhO2S
MeMgBr, THF,
0 °C to rt, 6 h
Na-Nap, THF
-78 °C, 5 min
O
O
O
O
NHBoc
NHBoc
93%
69% from 9
OMe
OMe
8
12
Scheme 2. Synthesis of key cyclohexene intermediate 8.
According to the retrosynthetic analysis, we needed
transposition of the olefin that would provide a strong platform to
perform a highly stereospecific installation of C3 and C4
hydroxy groups by cis-dihydroxylation protocol. In this context,
there was an urgent need of a temporary installation of ketone
functionality at the C2 position that will drive a pseudo olefin to
relocate the original olefin at the decided place. With the key
intermediate 8 in hand, we proceeded to develop a concise route
to prepare the crucial intermediate 7 which will provide C2, C3
and C4 hydroxy functionality by a dehydrogenative oxidation
followed by ketone reduction and finally cis-dihydroxylation. To
attempt the Wacker-type oxidation of internal olefins,14 a copper-
free protocol15 utilizing 0.9 equiv benzoquinone and 5 mol%
Pd(OAc)2 proved effective to prepare 7 in 56% yield (99% brsm).
synthetic
exploration
of
the
optically
pure
7-
11
azabicyclo[2.2.1]heptanone scaffold 9 which could be alluded
by a stereoselective Michael addition on corresponding enol
tosylate of 9 by using appropriately functionalized aromatic
nucleophile followed by facially biased hydrogenation of olefin
and subsequent ring opening due to existing strain in the ring.
Scheme 1. Retrosynthetic analysis.
2. Results and Discussion
Scheme 3. Systematic installation of three contiguous
hydroxyl groups over the C- ring.
As we have mentioned in our previous synthesis,11,13 the
appreciable amount of the supply of the optically pure 9 in hand,
drew our attention to develop a scalable preparation of the
required cyclohexane ring having great extent of functionality
and stereochemistry of the intermediate 8. Michael addition using
Grignard reagent 10 in the presence of copper iodide on the enol
tosylate of 9 (prepared by trapping its sodium enolate with tosyl
anhydride) followed by facially selective hydrogenation gave 11.
The intermediate 11 became the original source for the trans-
geometry of B-C ring junction present in the molecule and the
anion generated at the alpha carbon center of sulphone group
could promote the release of the strain in the ring. As a
Dehydrogenation of the ketone was accomplished by forming
corresponding silyl enol ether of parent carbonyl compound 7
followed by oxidation with IBX.MPO (iodoxybenzoic acid
complexed with 4-methoxypyridine-N-oxide) using pyridine and
DMSO as a solvent, which led to the formation of 13 (67%
16
yield).14, The major regioisomer 13 was isolated by column
chromatography and utilized further to install C2 hydroxy group.
Luche reduction (NaBH4, CeCl3.H2O) of 13 provided 14 as a
single diastereomer which was subjected to Mitsunobu18
condition (DEAD, PPh3 in THF and para nitro benzoic zcid,

3
PNB-OH) to invert C2 hydroxy configuration to obtain pseudo
trans-axial stereochemistry in the final molecule. Anti-orientation
of C2 and C4 substitution governed the stereoselective cis-
dihydoxylation of 15, using catalytic amount of OsO4, furnishing
fully functionalized C-ring (intermediate 16) as a single
diastereomer.
Hz. Peak multiplicity was indicated as follows: s (singlet), d
ACCEPTED MANUSCRIPT
(doublet), t (triplet), q (quartet), m (multiplet) and br. (broad). IR
spectra were recorded in a Perkin Elmer FT-IR Spectrum 2
spectrometer and the samples were either prepared as a thin film
on NaCl plates or incorporated into a KBr pellet. The spectra
were reported in cm−1. High resolution mass spectra were
obtained on an Agilent Technologies 6530 Accurate Mass Q-TOF
LC/MS device using electrospray ionization (ESI). Mass spectra
were recorded in positive ionization mode. Optical rotation was
measured in a Rudolph Instruments DigiPol 781 M6U Nova
automatic polarimeter.
4.2. Experimental detailsand characterisation data
4.2.1. (1S,2R,3R,4R)-tert-butyl 2-(7-
methoxybenzo[d][1,3]dioxol-5-yl)-3-(phenylsulfon
yl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (11)
Scheme 4. Formation of B ring and synthesis of (+)-trans-
dihydronarciclasine.
⁰
To the cooled solution (0 C) of NaH (1.71g, 60% suspension
in paraffin, 42.7 mmol, 1.5 equiv) in dry THF (10 mL) was added
the solution of 9 (10.0 g, 28.5 mmol,1.0 equiv) in dry THF (100
mL). After addition, the reaction mixture was stirred for 30
minutes and the solution of Ts2O (11.6 g, 35.6 mmol, 1.3 equiv)
in dry THF (120 mL) was transferred via cannula to the reaction
mixture over a period of 30 minutes. The solution was stirred for
a further 1 h at this temperature and quenched by the addition of
ice. It was stirred for 30 minutes and brine solution was added.
The two layers were separated and the aqueous layer was washed
with EtOAc (2 x 10 mL). The combined organic layer was dried
over sodium sulfate, concentrated and dried in vacuo and used
further for the next step without purification.
The free hydroxyl groups were protected by acetylation using
Ac2O in pyridine to obtain 17 which was subjected to Banwell’s
modified Bischler-Napieralski protocol19 to produce lactam
moiety of the B ring. Demethylation (BBr3, CH2Cl2, 0 °C)
followed
by
saponification
produced
(+)-trans-
dihydronarciclasine [[α]20.5 = +4.8° (c 0.15, THF); lit. [α]20
=
D
D
+4.7° (c 0.27, THF)].5a
3. Conclusions
In conclusion, we have delineated the asymmetric total
synthesis (+)-trans-dihydronarciclasine showing that 9 became a
pivotal synthetic intermediate for the preparation of
Amaryllidaceae isocarbostyrils with the synthesis diverging from
key cyclohexene 8. More importantly, the existing ring strain in 9
provides a great opportunity to get substituted cyclohexane ring
embedded with an olefin which will be utilized further in
diversification of various functionalities over cyclohexane ring.
The overall synthetic programme is amenable to generate rational
synthetic route towards the related alkaloids.
The Grignard reagent 10 (42.7 mL, 1.0 M solution in THF,
72.7 mmol, 1.5 equiv, prepared from the corresponding aryl
bromide20 and magnesium turnings in dry THF, made up to a 1.0
M stock solution.) was added to the solution of crude enol
tosylate in dry THF (100 mL) at 0 °C in the presence of catalytic
amount of CuI (271 mg, 1.42 mmol, 0.05 equiv).The reaction
mixture was warmed to rt and stirred for 12 h until the reaction
was completed. The reaction was cooled to 0 °C and quenched
with satd. aq. NH4Cl. The layers were separated and the aqueous
layer was washed with EtOAc (2 x 10 mL). The combined
organic layer was washed with distilled water (2 x 20 mL) and
with brine (1 x 5 mL), dried over sodium sulfate and
concentrated in vacuo.
4. Experimental
4.1. General information
The residue was taken in 200 mL MeOH and stirred it for 5
minutes. The mixture was filtered through a pad of celite and
washed with a 50 mL MeOH. To the combined filtrate was added
10 % Pd/C (3 g, 2.9 mmol, 0.1 equiv) and the reaction mixture
was stirred at >1000 rpm under hydrogen at atmospheric
pressure. The reaction was monitored peridically by TLC till
completed (12 h). The reaction mixture was filtered through a
pad of celite, concentrated in vacuo to obtain crude 11 and
proceeded for the next step without column purification.
Reagents and solvents were purchased from commercial
sources (Aldrich, Acros, Merck, Fluka and Spectrochem) and
preserved under argon. More sensitive compounds were stored in
a vacuum desiccator. Reagents were used without further
purification unless otherwise noted. All reactions were performed
under argon and stirring unless otherwise noted. All glassware
was dried overnight in an oven (T > 110 °C) or under vacuum
with a heat gun (T > 200 °C). Flash column chromatography was
performed using Aldrich 60 Å silica: 200-400 mesh 40 – 75 ꢀm
silica gel. Reactions were monitored using Merck Kieselgel
60F254 aluminium plates. TLC were visualized by UV
fluorescence (254 nm) one of the following: KMnO4,
phosphomolybdic acid, ninhydrin, p-anisaldehyde. NMR spectra
were recorded on a Brüker Avance III-800, Brüker Avance III-
600 HD and Brüker Avance-400 HD spectrometers at room
tert-butyl
[(1S,2R)-2-(7-methoxybenzo[d][1,3]dioxol-5-yl)-3-
(phenylsulfonyl)cyc lohx-3-en-1-yl]carbamate (12)
To a stirred ice cooled solution of crude 11 in dry THF (200
mL) was added MeMgBr solution (1.4M in THF/toluene, 60.9
mL, 85.4 mmol, 3.0 equiv) dropwise over a period of 30 minutes
so as to avoid excess foaming. After addition was completed, the
ice bath was removed and the solution was allowed to stirr at
ambient temperature for 24 h until the TLC showed the
completion of the reaction. The reaction mixture was cooled in
ice bath once more and satd. aq. NH4Cl (100 mL) solution was
added carefully with vigorous stirring. The reaction mixture was
diluted by 100 mL water to dissolve the white magnesium salts
1
temperature. H frequency was at 800.21 MHz and 400.13 MHz
and 13C frequency was at either 201 MHz, 151 MHz or 101 MHz.
Chemical Shifts (δ) were reported in parts per million (ppm)
relative to residual solvent peaks rounded to the nearest 0.01 for
proton and 0.1 for carbon (ref: CHCl3 [1H: 7.27, 13C: 77.0];
MeOD [1H: 4.87, 13C: 49.2]; DMSO-d6 [1H: 2.50, 13C: 39.5]).
Coupling constants (J) were reported in Hz to the nearest 0.01

4
Tetrahedron
ACCEPTED MANUSCRIPT
and after addition of brine the two layers were separated. The
(dd, J = 1.3, 3.4 Hz, 2H), 6.40 (s, 1H), 6.43 (d, J = 1.34 Hz, 1H);
aqueous layer was washed with EtOAc (2 x 10 mL). The
combined organic layer was dried over sodium sulfate,
concentrated in vacuo and purified via silica gel chromatography
(ethyl acetate:hexane, 3:7) to obtain 12 as a white solid (9.6g,
69.2%) m.p.: 233-236 oC; [α]D20.6 = +67.2 (c = 1.4 in CHCl3); IR
13C NMR (101 MHz, CDCl3): δ = 28.1, 31.1, 31.7, 39.5, 40.8,
48.1, 48.5, 49.5, 52.3, 53.9, 56.6, 79.5, 101.3, 101.5, 106.9,
134.1, 134.2, 135.5, 136.0, 143.5, 143.6, 148.9, 149.0, 154.7,
155.1, 207.9, 208.5; HRMS (ESI): calcd. for [C19H25NO6 + Na+]:
386.1574, found: 386.1576.
(CHCl3): 3436, 2933, 1700, 1510, 1046, 759 cm-1; H NMR(800
1
4.2.4. tert-butyl [(1S,6R)-6-(7-methoxybenzo[d][1,
3]dioxol-5-yl)-4-oxocyclohex-2-en-1-yl]carbamate
(13)
MHz, CDCl3): δ = 1.38 (s, 9H), 1.55-1.65 (m, 1H), 1.66-1.74 (m,
1H), 2.33-2.43 (m, 1H), 2.44-2.53 (m, 1H), 3.72 (s, 3H), 3.82 (br.
s, 1H), 3.88 (s, 1H), 4.60-4.69 (m, 1H), 5.79 (d, J = 40.7 Hz, 2H),
6.01 (s, 1H), 6.08 (s, 1H), 7.25-7.32 (m, 1H), 7.39-7.45 (m, 2H),
7.54 (d, J = 7.5 Hz, 2H); 13C NMR(201 MHz, CDCl3): δ = 19.8,
21.8, 28.4, 45.4, 51.4, 56.6, 79.8, 101.4, 102.8, 108.2, 128.1,
128.6, 132.9, 133.5, 134.1, 140.0, 140.2, 140.7, 143.2, 148.5,
155.1; HRMS (ESI) calcd. For [C25H29NO7S + Na+]: 510.1557
found: 510.1545.
To a cooled (0 °C) solution of diisopropylamine (0.58 mL, 4.1
mmol, 3 equiv) in dry THF (5 mL) was added nBuLi solution
(1.6 mL, 2.5 M in hexanes, 4.1 mmol, 3 equiv) and stirred for 10
minutes. A solution of 7 (0.5 g, 1.4mmol, 1.0 equiv.) in dry THF
(10 mL) was added dropwise to the LDA solution at 0 ˚C and
stirred it for 1 h at that temperature. TMSCl (0.52 mL, 4.1 mmol,
3.0 equiv) was added dropwise, the reaction mixture was stirred
for an additional 30 minutes and quenched by adding 5 g of
crushed ice. The reaction mixture was diluted by diethyl ether
(20mL) and brine was added. The layers were separated and the
aqueous layer was extracted with diethyl ether (3 x 10 mL). The
combined organic layer was washed with distilled water (2 x 10
mL) followed by brine (5 mL) and dried over anhydrous sodium
sulfate before concentrating in vacuo. The crude silyl enol ether
was used without further purification.
4.2.2. tert-butyl[(1S,2R)-2-(7-
methoxybenzo[d][1,3]dioxol-5-yl)cycloh ex-3-en-1-
yl] carbamate (8)
Sodium naphthalenide (Na-Nap) was prepared by adding
sodium metal (2.3 g, 100 mmol, 10.0 equiv, ~2.0 mm sized
pieces) to the degassed solution of naphthalene (3.9 g, 30.0
mmol, 3.0 equiv) in dry THF (300 mL) and stirred at rt for 3
hours. The dark green Na-Nap solution was added to the solution
of 12 (10.0 mmol, 1.0 equiv) in dry THF (200 mL) by cannula
transfer at -78 °C. After addition was completed, immediately the
reaction mixture was quenched by the addition of satd. aq. NH4Cl
and warmed it to rt. The two layers were separated and the
aqueous layer was washed with EtOAc (2 x 30 mL). The
combined organic layer was dried over anhydrous sodium sulfate
and concentrated in vacuo. The crude residue was purified by
silica gel chromatography (ethyl acetate:hexane 1:9) to give 8 as
a white solid (3.25 g, 93%) m.p.: 121-124 °C; [α]D20.5 = + 96.0 (c
= 1.09 in CHCl31); IR (CHCl3): 3361, 1687, 1634, 1432, 1367,
1048, 774 cm-1; H NMR(800 MHz, CDCl3): δ = 1.39 (s, 9H),
1.57-1.64 (m, 1H), 1.86-1.95 (m, 1H), 2.11-2.19 (m, 1H), 2.19-
2.27 (m, 1H), 3.21 (br. s, 1H), 3.64-3.75 (m, 1H), 3.89 (3H), 4.64
(br. s, 1H), 5.60 (d, J = 9.0 Hz, 1H), 5.86-5.90 (m, 1H), 5.93 (dd,
J = 1.5, 5.0 Hz, 2H), 6.42 (s, 1H), 6.45 (s, 1H); 13C NMR (201
MHz, CDCl3): δ =22.9, 25.6, 28.1, 47.8, 52.1, 56.4, 78.9, 101.1,
102.4, 107.5, 127.9, 133.6, 137.3, 143.2, 148.5, 155.1; HRMS
(ESI) calcd. for [C19H25NO5 + Na+]: 370.1625, found: 370.1620.
The solution of iodoxybenxoic acid (IBX) and 4-methoxy
pyridine N-oxide (MPO) in DMSO (3 mL) was stirred at rt until
a clear solution formed (30 min). The IBX.MPO complex was
added to the silyl enol ether-pyridine (1.1 mL, 13.8 mmol, 10.0
equiv) solution in DMSO (5 mL). The resulting solution was
stirred for an additiional 1 h. The solution was diluted with
EtOAc (50 mL) and satd. Aq. NaHCO3 was added ( 5mL). The
layers were separated and the organic layer was washed with
distilled water (3 x 10 mL) followed by brine (5 mL) and dried
over anhydrous sodium sulfate. The solution was concentrated in
vacuo and purified by silica gel column chromatography (7:3
hexane:EtOAc) to obtain 13 as a white solid (333 mg, 67%)
along with its regioisomer (47 mg, 9%). m.p.: 168 - 170 °C;
[α]D21.2 = - 6.5 (c = 1.09 in CHCl3); IR (CHCl3): 3430, 1644, 995,
755, 654, 503 cm-1; 1H NMR (400 MHz, CDCl3):δ =1.35 (s, 9H),
2.62-2.70 (m, 2H), 3.11-3.25 (m, 1H), 3.89 (s, 3H), 4.55 (br. s,
1H), 4.65-4.77 (m, 1H), 5.94 (s, 2H), 6.04 (dd, J = 2.5, 10.3 Hz,
1H), 6.37-6.46 (m, 2H), 6.91 (d, J = 9.9 Hz, 1H); 13C NMR (101
MHz, CDCl3): δ = 28.1, 31.7, 39.5, 44.9, 48.0, 49.6, 56.6, 79.6,
80.0, 101.4, 107.2, 129.1, 134.5, 135.5, 143.5, 149.1, 152.3,
155.2, 197.6; HRMS (ESI): calcd. for [C19H23NO6 + Na+]:
384.1418, found: 384.1421.
4.2.3. tert-butyl[(1S,2R)-2-(7-methoxybenz o[d] [1,
3]dioxol-5-yl)-4-oxocyclohexyl] carbamate (7)
Pd(OAc)2 (32.3 mg, 0.14 mmol, 0.05 equiv), 99% H2SO4
(0.23 mL, 4.3 mmol, 1.5 equiv) and 1,4-benzoquinone (280.0
mg, 2.6 mmol, 0.9 equiv) were dissolved in acetonitrile/water
(7:1 v/v, 200 mL) . The resulting solution was degassed by the
freeze-pump-thaw method (3 cycles). To the clear, degassed
solution was added 8 (1.0 g, 2.9 mmol, 1.0 equiv) and stirred at
rt for 24 h. To the reaction mixture was added brine (20 mL) and
stirred vigorously. The two layers were separated and the
aqueous layer was washed with EtOAc (2 x 50 mL). The organic
layer was combined and washed with brine (3 x 20 mL) till to
neutral pH. The organic layer was dried over anhydrous sodium
sulfate and immediately concentrated in vacuo. The resulting
solid was purified immediately by column chromatography (9:1
hexane:EtOAc, 7:3 hexane:EtOAc) to obtain recovered 8 (460
mg 46% of starting material, 54% conversion) and 7 as a white
4.2.5. tert-butyl[(1S,4R,6R)-4-hydroxy-6-(7-methox
ybenzo[d][1,3]di oxol-5-yl) cyclohe x-2-en-1-
yl]carbamate (14)
To a round bottom flask containing 13 (0.1 g, 0.28 mmol, 1.0
equiv) and CeCl3.7H2O (0.31 g, 0.83 mmol, 3.0 equiv) in distilled
methanol (10 mL) was added NaBH4 (10.5 mg, 0.28 mmol, 1.0
°
equiv) at 0 C in a single portion. The reaction mixture was
stirred at that temperature for 10 min and it was quenched with
satd. aq. ammonium chloride. The reaction mixture was diluted
with EtOAc (20 mL) and the layers were separated. The aqueous
layer was extracted with EtOAc (3 x 5 mL), the combined
organic layer was washed with brine (2 x 5 mL) and dried over
anhydrous sodium chloride. It was concentrated in vacuo and
purified by column chromatography (ethyl acetate:hexane 1:1) to
give 14 (100 mg, 99% yield) as a white crystalline solid. m.p.:
188 – 190 ˚C; [α]D21.2 = + 50.1 (c = 0.75 in MeOH). IR (CHCl3):
21.2
solid (560 mg, 99% brsm). m.p.: 178 - 182 °C; [α]D = + 28.9
(c = 0.55 in CHCl3); IR (CHCl3): 3438, 2922, 1620, 1384, 1091,
1043 cm-1; H NMR (400 MHz, CDCl3): δ =1.36 (s, 9H), 1.63-
1
3413, 1628, 1472, 1340, 1029, 750 cm-1; H NMR (400 MHz,
1
1.76 (m, 1H), 2.41-2.52 (m, 2H), 2.52-2.61 (m, 2H), 2.78-2.88
(m, 1H), 3.91 (s, 3H), 4.00-4.14 (m, 1H), 4.25-4.36 (m, 1H), 5.95
CDCl3):δ = 1.33 (s, 9H), 1.75-1.88 (m, 1H), 2.19-2.32 (m, 1H),

5
2.52-2.72 (m, 1H), 3.89 (s, 3H), 4.17-4.31 (m, 1H), 4.37-4.51 (m,
1H), 5.67-5.77 (m, 1H), 5.77-5.86 (m, 1H), 5.93 (d, J = 1.1 Hz,
2H), 6.37-6.46 (m, 2H); 13C NMR (101 MHz, CDCl3):δ = 28.5,
30.0, 56.9, 68.1, 101.6, 101.8, 131.8, 132.7, 134.3, 137.0, 143.7,
149.2, 155.5; HRMS (ESI): calcd. for [C19H23NO6 + Na+]:
386.1574, found: 386.1578.
Acetic anhydride (79.0 µL, 0.84 mmol, 5.0 equiv) was added
ACCEPTED MANUSCRIPT
dropwise to the solution of 16 (92.0 mg, 0.17 mmol, 1.0 equiv) in
dry pyridine (10 mL) at 0 ˚C in presence of DMAP (10.0 mg,
0.084 mmol, 0.50 equiv). The solution was stirred for 1 h until
the reaction was completed and quenched with the addition of 5 g
crushed ice. The reaction mixture was diluted by DCM (20 mL),
brine was added and the two layers were separated. The aqueous
layer was extracted with DCM (3 x 5 mL) and the combined
organic layer was washed with distilled water (3 x 5 mL), dried
over anhydrous sodium sulfate and concentrated in vacuo to give
a white solid. The crude 17 was found to be of sufficient pure to
4.2.6. (1S,2S,3S,4R,5R)-4-[(tert-butoxycarbon yl )a
mino] -2,3-dihydroxy -5-(7-methoxyb enzo [d][1,3]
dioxol-5-yl)cyclohexyl 4-nitroben zoate (16)
To the solution in dry THF (8 mL) containing 14 (0.04 g, 0.11
mmol, 1.0 equiv) ,triphenylphosphine (116 g, 0.44 mmol, 4
equiv) and p-nitrobenzoic acid (PNB-OH) (74.0 mg, 0.44 mmol,
4.0 equiv) was added diisopropyl azodicarboxylate (DIAD) (86.0
µL, 0.44 mmol, 4.0 equiv) at 0 ˚C. The reaction mixture was
stirred at 0 ˚C for 30 min, allowed to warm to rt and stirred for an
additional 24 h. The reaction mixture was cooled to 0 ˚C,
quenched with satd. aq. NaHCO3 (5 mL) and diluted with EtOAc
(20 mL). The layers were separated and the aqueous layer was
extracted with EtOAc (2 x 5 mL). The combined organic layer
was dried over anhydrous sodium sulfate and concentrated in
vacuo. The crude material was eluted from a short column with
EtOAc:hexane (1:4) and concentrated in vacuo. The product
contained a impurity after column chromatography and the
impure product was used directly in the next step. A small
amount of pure 15 was obtained by recrystallizing from
20.7
proceed with the next step. [α]D = + 22.2 (c = 0.25 in CHCl3).
IR (CHCl3): 3419, 1733, 1530, 1240, 1056, 668 cm-1; H NMR
1
(400 MHz, CDCl3):δ =1.29 (s, 9H), 2.04 (s, 3H), 2.14-2.21 (m,
2H), 2.24 (s, 3H), 2.94 (dd, J = 8.6, 19.1 Hz, 1H), 3.89 (s, 3H),
4.17 (q, J = 10.64 Hz, 1H), 4.38 (d, J = 9.9 Hz, 1H), 5.28-5.39
(m, 2H), 5.46-5.54 (m, 1H), 5.92 (dd, J = 1.2, 6.5 Hz, 2H), 6.43
(s, 2H), 8.24 (d, J = 8.8 Hz, 2H), 8.32 (d, J = 8.9 Hz, 2H); 13C
NMR (101 MHz, CDCl3): δ = 20.7, 21.0, 28.1, 33.6, 43.5, 52.3,
56.6, 68.9, 70.5, 71.0, 79.4, 101.4, 101.8, 107.1, 123.7, 130.9,
134.1, 134.7, 143.4, 148.9, 150.8, 155.2, 163.1, 170.6, 169.5 ;
HRMS (ESI): calcd. for [C30H34N2O13 + Na+]: 653.1953, found:
653.1951.
To the solution of 17 in dry DCM (10 mL) was added 2-
chloropyridine (32.0 µL, 0.34 mmol, 2.0 equiv) and cooled it to -
84 ˚C. Tf2O was added dropwise (0.85 mL, 10% solution in
DCM, 0.51 mmol, 3 equiv). After stirring for 30 minutes,
BF3.OEt2 was added and the reaction mixture was allowed to
warm to rt over 12 hours. The reaction mixture was treated with
satd. aq. NaHCO3 and stirred for 10 min. The two layers were
separated, the aqueous layer was extracted with EtOAc (3 x 5
mL). The combined organic layer was dried over anhydrous
sodium sulfate and concentrated in vacuo. The crude product was
purified by flash column chromatography (ethyl acetate:hexane
2:1) to give the major isomer 18 (63 mg, 67% yield) as a pale
20.7
EtOAc:hexane (1:9) for analysis. m.p.: 190 – 191 ˚C; [α]D = -
35.5 (c = 0.75 in CHCl3). IR (CHCl3): 2933, 2866, 1763, 1529,
1
1259, 1000, 653 cm-1; H NMR (400 MHz, CDCl3):δ = 1.35 (s,
9H), 2.19-2.27 (m, 2H), 2.83-2.96 (m, 1H), 3.92 (s, 3H), 4.30 (br.
s, 1H), 4.50 (br. s, 1H), 5.54-5.60 (m, 1H), 5.94 (s, 2H), 5.98-
6.05 (m, 1H), 6.06-6.15 (m, 1H), 6.42-6.47 (m, 2H), 8.19-8.27
(m, 2H), 8.27-8.35 (m, 2H); 13C NMR (101 MHz, CDCl3):δ =
28.2, 56.7, 68.1, 101.3, 101.7, 123.6, 124.8, 130.7, 134.2, 135.8,
136.3, 136.9, 143.5, 149.1, 150.6, 155.2, 164.1; HRMS (ESI):
calcd. for [C26H28N2O9 + Na+]: 535.1687, found: 535.1690.
yellow solid along with the minor isomer (9 mg, 10% yield).
To the solution of crude product in THF (5 mL) was added
methane sulfonamide (31.0 mg, 0.33 mmol, 3.0 equiv), 4-
methylmorpholine N-oxide (NMO) (69 µL, 50% solution in H2O,
0.33 mmol, 3 equiv) and OsO4 (110 µL, 0.05 M solution in t-
BuOH, 5.5 µmol, 0.05 equiv) and the reaction mixture was
stirred till the reaction was completed (48 h). The reaction
mixture was diluted with EtOAc (10 mL), quenched with satd.
aq. Na2SO3 (5mL) and stirred vigorously for 10 min. The two
layers were separated and the aqueous layer was extracted with
EtOAc (3 x 5 mL). The combined organic layer was dried over
sodium sulfate and concentrated in vacuo. The crude product was
purified by flash column chromatography (ethyl acetate:hexane
2:1) to give pure 16 as a white solid (59 mg, 98% yield from 14).
21.1
[α]D
= + 61.2 (c = 0.5 in CHCl3). IR (CHCl3):, 3280, 3051,
1916, 1649, 1489, 998, 750 cm-1; 1H NMR (400 MHz, CDCl3): δ
= 1.99-2.08 (m, 1H), 2.11 (s, 3H), 2.12 (s, 3H), 2.56 (dt, J = 3.2,
14.6 Hz, 1H), 3.12 (td, J = 3.9, 12.5 Hz, 1H), 3.74 (t, J = 11.3 Hz,
1H), 4.06 (s, 3H), 5.26-5.34 (m, 1H), 5.44-5.51 (m, 1H), 5.56-
5.62 (m, 1H), 5.99 (dd, J = 1.2, 12.5 Hz, 2H), 6.49 (s, 1H), 6.97
(br. s, 1H), 8.20-8.26 (m, 2H), 8.29-8.35 (m, 2H); 13C NMR (101
MHz, CDCl3): δ = 21.0, 21.1, 36.4, 52.2, 61.1, 67.5, 70.4, 71.6,
99.2, 102.1, 115.6, 124.1, 131.3, 134.7, 137.3, 137.5, 145.4,
151.2, 152.5, 163.5, 164.7, 169.5, 170.8; HRMS (ESI): calcd. for
[C26H24N2O12 + Na+]: 579.1221, found: 579.1228.
4.2.8. (2S,3R,4S,4aR,11bR)-2,3,4,7-tetrahydroxy-1,
3,4,4a,5,11b-hexahydro-[1,3]dioxol o[4,5-j]phenan
thridin-6(2H)-one[(+)-trans-dihydronarciclasine]
(1)
21.3
m.p.: 190 – 191 ˚C; [α]D = + 105.1 (c = 0.35 in CHCl3). IR
(CHCl3): 3269, 1930, 1651, 1311, 1153, 988 cm-1; 1H NMR (800
MHz, DMSO-d6): 0.81 (s, 9H), 1.38 (d, J = 14.1 Hz, 1H), 1.75 (t,
J = 13.6 Hz, 1H), 2.90-2.98 (m, 2H), 3.23-3.31 (m, 1H), 3.32-
3.37 (m, 1h), 3.39 (s, 3H), 3.50 (br. s, 1H), 4.04 (d, J = 7.0, 1H),
4.73 (br. s, 1H), 4.97 (d, J = 4.0 Hz, 1H), 5.47 (s, 2H), 6.03 (s,
1H), 6.09 (s, 1H), 7.87 (d, J = 8.5, 2H), 7.95 (d, J = 8.5); 13C
NMR (201 MHz, DMSO-d6): 27.9, 28.1, 31.8, 54.0, 56.0, 69.6,
70.5, 73.6, 76.9, 100.8, 101.9, 107.6, 123.8, 130.9, 133.0, 135.3,
142.7, 148.0, 150.4, 155.5, 163.3; HRMS (ESI): calcd. for
[C26H30N2O11 + Na+]: 569.1742, found: 569.1746.
To the solution of 18 (26.0 mg, 0.047 mmol, 1.0 equiv) in dry
DCM (5 mL) was added BBr3 (70.0 µL, 1M solution in DCM,
0.070 mmol, 1.5 equiv) at 0 ˚C. The solution was stirred for 1 h
at that temperature and quenched with 2 mL NH4OH (28% NH3
in H2O). The reaction mixture was diluted with EtOAc (20 mL),
washed with brine and the two layers were separated. The
aqueous layer was extracted with EtOAc (5 x 5 mL), the
combined organic layer was dried over anhydrous sodium sulfate
and concentrated in vacuo and dried at 0.04 Torr for 1 h at 50 ˚C.
The crude product was used directly in the following step.
4.2.7. (2S,3R,4S,4aR,11bR)-7-methoxy-2-[(4-nitro
benzoyl)oxy] -6-oxo-1,2,3,4,4a,5,6,11b-octahydro-
[1,3]dioxolo[4,5-j]phenanth ridine-3,4-diyl
diacetate (18)
To the solid obtained was added MeOH (5 mL), NaOMe (25.0
mg, 0.467 mmol, 10.0 equiv) in a single portion and the solution
was stirred for 30 min. The reaction mixture was quenched with

6
Tetrahedron
ACCEPTED MANUSCRIPT
k) McNulty J, Mo R. Chem. Commun. 1998;933–935;
l) Pettit GR, Pettit III GR, Backhaus RA, Boyd MR, Meerow AW.
J. Nat. Prod. 1993; 56:1682–1687;
m) Pettit GR, Gaddamidi, V, Herald DL, Singh SB, Cragg GM,
Schmidt JM, Boettner FE, Williams M, Sagawa Y. J. Nat. Prod.
1986;49:995–1002;
n) Pettit GR, Gaddamidi V, Cragg GM, Herald DL, Sagawa Y. J.
Chem. Soc. Chem. Commun. 1984;1693–1694.
satd. aq. NH4Cl (5 mL) and extracted with EtOAc (5 x 5 mL).
The combined organic layer was dried over sodium sulfate and
concentrated in vacuo. The resulting solid was purified by flash
column chromatography (10% MeOH in EtOAc) to give trans-
dihydronarciclasine (1) as a white solid (12 mg, 83% yield).
20.5
[α]D = + 4.8 (c = 0.15 in THF). IR (neat): 3315, 2955, 1668,
1626, 1410, 1341, 1030 cm-1; H NMR (400 MHz, CD3OD): δ =
1
3. Mondon A, Krohn K. Chem. Ber. 1975;108:445–463.
4.
1.78–1.87 (m, 1H), 2.18-2.27 (m, 1H), 2.96 (td, J = 3.4, 12.8 Hz,
1H), 3.44 (dd, J = 10.5, 13 Hz, 1H), 3.85 (dd, J = 3.1, 10.2 Hz,
1H), 3.91 (t, J = 2.9, 1H), 4.06-4.11 (m, 1H), 6.00 (dd, J = 1.1,
3.4 Hz, 2H), 6.45 (d, J = 0.9 Hz, 1H); 13C NMR (151 MHz,
CD3OD): 30.2, 35.8, 56.9, 71.1, 72.1, 73.9, 98.3, 104.0, 108.8,
134.5, 140.3, 147.8, 154.9, 172.5; HRMS (ESI): calcd. for
[C14H15NO7 + Na+]: 332.0741, found: 332.0748.
Pettit GR, Cragg GM, Singh SB, Duke JA, Doubek DL. J. Nat.
Prod. 1990;53:176–178.
a) Pettit GR, Eastham SA, Melody N, Orr B, Herald DL,
McGregor J, Knight JC, Doubek DL, Pettit III GR, Garner LC,
Bell JA. J. Nat. Prod. 2006;69:7-13;
b) Pettit GR, Melody N. J. Nat. Prod. 2005;68:207-211.
a) McNulty J, D’Aiuto L, Zhi Y, McClain L, Zepeda-Velazquez
C, Ler S, Jenkins HA, Yee MB, Piazza P, Yolken RH,
Kinchington PR, Nimgaonkar VL. ACS Med. Chem. Lett.
2016:7:46–50;
5.
6.
b) Gabrielsen B, Monath TP, Huggins JW, Kefauver DF, Pettit
GR, Groszek G, Hollingshead,, M, Kirsi JJ, Shannon WM,
Schubert EM, DaRe J, Ugarkar B, Ussery M, Phelan MJ. J. Nat.
Prod. 1992;55:1569– 1581.
a) Varre G, Hegedus L, Simon A, Kadas I. Tetrahedron Lett.
2016;57:1544–1546; b) Cho YS, Cho CG. Tetrahedron
2008;64:2172–2177;
Acknowledgments
We thank the Department of Science & Technology (DST), New
Delhi through the J. C. Bose Fellowship for generous financial
support. D. D., R. F and B. M. thank the Council of Scientific
and Industrial Research (CSIR) and the University Grants
Commission (UGC), respectively, for their fellowships.
7.
8.
c) Shin IJ, Choi ES, Cho CG. Angew. Chem. Int. Ed.
2007;46:2303–2305.
a) Revu O, Zepeda-Velazquez C, Nielsen A, McNulty J, Yolken
RH, Jones-Brando L. ChemistrySelect. 2016;1:5895-5899;
b) Hwang S, Kim D, Kim S, Chem. Eur. J. 2012;18:9977–9982;
c) Yamada K, Mogi Y, Mohamed M, Takasu K, Tomioka K. Org.
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Supplementary Material
d) Jana CK, Studer A. Chem. Eur. J. 2008;14:6326–6328.
1H and 13C NMR spectra for all compounds 1, 7, 8, 12-18.
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7
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